Chronic inflammation, anti-inflammatory treatment and risk of malignant lymphomas

The aim of this thesis was to investigate the link between malignant lymphomas and chronic inflammation, in particular the associations between inflammatory activity, immune-modulatory treatment and risk of lymphoma development. To address this aim, we used Swedish population-based registers, mandatory cancer reporting and nation-wide clinical registers including the Swedish Rheumatology Register (SRQ). In study I we investigated whether patients with rheumatoid arthritis (RA) are at increased risk of lymphoma or cancer overall before clinical onset of RA, and if this risk increases with time since RA diagnosis. A cohort of 6,745 incident RA patients (1997-2006) was identified using data from the SRQ. Each cohort member was matched to five population comparator subjects. Relative risks of lymphoma and cancer overall before and after diagnosis of RA were estimated. We observed no increased risks before diagnosis of RA whereas during the first ten years following diagnosis, the lymphoma risk was almost doubled with a non-significant trend of increasing risks with longer RA disease duration. In study II with a larger study population and with longer follow-up, we set out to assess whether the lymphoma risk remains elevated in RA patients diagnosed in the last few years and to explore potential risk predictors in relation to disease characteristics and therapy, focusing on the first year following RA diagnosis. Through SRQ, a cohort of 10,367 incident RA patients (1997-2010) was assembled. Each patient was matched to five population comparator subjects. The risk of lymphoma in recently diagnosed RA patients remained increased to the same magnitude as that reported from historical RA cohorts without any change in risk in recent years. The results indicated that inflammatory activity during the 1st year following RA diagnosis correlated with higher lymphoma risk, whereas oral glucocorticoids were associated with a reduced risk. Exposure to tumor necrosis factor inhibitor (TNFi) during the study period was not associated with increased lymphoma risk. Through histopathological classification, we further noted an increased proportion of Hodgkin lymphoma and diffuse large B-cell lymphoma and a decreased proportion of chronic lymphocytic leukemia in RA patients compared with the general population. In study III the relationship between treatment with glucocorticoids and lymphoma risk in RA patients was investigated in a case-control study. From a nationwide cohort of 74,651 prevalent RA patients 1964-1994, 378 RA patients with lymphoma and 378 matched RA controls were identified. Different aspects of glucocorticoid treatment were abstracted from medical records. Treatment with glucocorticoids, oral as well as intra-articular, was associated with a reduced lymphoma risk. In study IV the underlying risks of lymphoma in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) were investigated, including risks in relation to disease characteristics and treatment. Nationwide prevalent cohorts of AS (n=8,707) and PsA (n=19,283) 2001-2010 were assembled. Each cohort member was matched to five population comparator subjects. On average, we observed no increased risks of lymphoma in AS or in PsA, although there was a risk increase in PsA patients treated with methotrexate and/or sulfasalazine. Based on small numbers there was no evidence of increased lymphoma incidence following therapy with TNFi in AS or in PsA patients

Temporal trends in adverse pregnancy outcomes in axial spondyloarthritis in Sweden : a cohort study

Background: Evidence on the risks associated with pregnancy and childbirth in women with axial spondyloarthritis is scarce and conflicting, with more research needed to guide policy and clinical practice. We aimed to assess the risks of adverse pregnancy outcomes in a large cohort of women with axial spondyloarthritis, and to investigate how outcomes varied over time and in relation to anti-rheumatic treatment. Methods: In this register-based cohort study, we included births in Sweden between April 1, 2007, and Dec 31, 2020, to women with axial spondyloarthritis and general population comparators, matched 1:10 on year of delivery, maternal age, and parity. Our main data source was the Medical Birth Register (MBR), which includes over 98% of births in Sweden and prospectively collects data on antenatal care, delivery, and foetal outcomes. The information in MBR was linked to other registers, including the National Patient Register, the Prescribed Drug Register, and registers with demographic data. Our main outcomes were the relative risks of adverse pregnancy outcomes, analysed using modified Poisson regression. We also studied how the frequency of certain adverse outcomes, as well as disease-modifying antirheumatic drug (DMARD) and non-steroidal anti-inflammatory drug treatments, changed over the study period by linear regression and loess plots. Findings: Between April 1, 2007, and Dec 31, 2020, 1580 births in women with axial spondyloarthritis recorded in MBR fulfilled the inclusion criteria and were matched with 15 792 comparator births. Among the 1580 births in women with axial spondyloarthritis, we found increased risks of preterm birth (risk ratio 1.43, 95% CI 1.13-1.80), pre-eclampsia (1.44, 1.08-1.92), elective caesarean delivery (1.59, 1.37-1.84), and serious infant infection (1.29, 1.05-1.59) compared with births in general population comparators. The risks of preterm birth, infant infection, and caesarean delivery decreased by around 0.5 percentage points annually during the study period, while the use of tumour necrosis factor inhibitors during pregnancy increased. Interpretation: In view of remaining concerns regarding safety of the use of biological DMARDs during pregnancy, we saw a reassuring trend in which pregnancy outcomes improved over time in the axial spondyloarthritis group, concurrent with increased use of biological DMARDs. If the current rate of improvement is maintained, women with axial spondyloarthritis treated in accordance with clinical guidelines might eventually not be at an increased risk of adverse pregnancy outcomes.NoneAccepte

Opportunities and challenges for real-world studies on chronic inflammatory joint diseases through data enrichment and collaboration between national registers : the Nordic example

RMD Open 2018;4:e000655. doi:10.1136/ rmdopen-2018-000655Peer reviewe

Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors : a Nordic cohort study

OBJECTIVES: To evaluate the risk of haematological malignancies in patients with psoriatic arthritis (PsA) overall, and in relation to treatment with tumour necrosis factor inhibitors (TNFi). METHODS: We identified that patients with PsA starting a first TNFi from the clinical rheumatology registers (CRR) in the five Nordic countries (n=10 621) and biologics-naïve PsA patients from (1) the CRR (n=18 705) and (2) the national patient registers (NPR, n=27 286, Sweden and Denmark) from 2006 through 2019. For Sweden and Denmark, general population comparators were matched 5:1 to PsA patients on birth year, year at start of follow-up and sex. By linkage to the national cancer registers in all countries, we collected information on haematological malignancies overall, and categorised into lymphoid or myeloid types. We estimated incidence rate ratios (IRRs) with 95% CIs using modified Poisson regression for TNFi-treated versus biologics-naïve PsA patients and versus the general population adjusted for age, sex, calendar period and country. RESULTS: During 59 827 person-years, 40 haematological malignancies occurred among TNFi-treated patients with PsA resulting in a pooled IRR of 0.96 (0.68-1.35) versus biologics-naïve PsA from CRR and an IRR of 0.84 (0.64-1.10) versus biologics-naïve PsA from NPR. The IRR of haematological malignancies in PsA overall versus general population comparators was 1.35 (1.17-1.55). The estimates were largely similar for lymphoid and myeloid malignancies. CONCLUSIONS: Treatment with TNFi in patients with PsA was not associated with an increased incidence of haematological malignancies. Conversely, a moderately increased underlying risk was seen in patients with PsA compared with the general population.publishedVersionPeer reviewe

a European registries collaborative project

Funding: Individual registries had entered into agreements with pharmaceutical companies (AbbVie, BMS, Hospira, MSD, Pfizer, Roche, UCB, Samsung and Eli Lilly). The pharmaceutical companies funding these registers were, however, not involved in the planning of the project, the statistical analyses, the interpretation of the results or the decision to publish.BACKGROUND: Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes. METHODS: Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD. RESULTS: Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population. CONCLUSION: This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.publishersversionpublishe

Tafoxiparin, a novel drug candidate for cervical ripening and labor augmentation : results from 2 randomized, placebo-controlled studies

Background: Slow progression of labor is a common obstetrical problem with multiple associated complications. Tafoxiparin is a depolymerized form of heparin with a molecular structure that eliminates the anticoagulant effects of heparin. We report on 2 phase II clinical studies of tafoxiparin in primiparas. Study 1 was an exploratory, first-in-pregnant-women study and study 2 was a dose-finding study. Objective: Study 1 was performed to explore the effects on labor time of subcutaneous administration of tafoxiparin before onset of labor. Study 2 was performed to test the hypothesis that intravenous treatment with tafoxiparin reduces the risk for prolonged labor after spontaneous labor onset in situations requiring oxytocin stimulation because of dystocia. Study Design: Both studies were randomized, double-blind, and placebo-controlled. Participants were healthy, nulliparous females aged 18 to 45 years with a normal singleton pregnancy and gestational age confirmed by ultrasound. The primary endpoints were time from onset of established labor (cervical dilation of 4 cm) until delivery (study 1) and time from start of study treatment infusion until delivery (study 2). In study 1, patients at 38 to 40 weeks of gestation received 60 mg tafoxiparin or placebo daily as 0.4 mL subcutaneous injections until labor onset (maximum 28 days). In study 2, patients experiencing slow progression of labor, a prolonged latent phase, or labor arrest received a placebo or 1 of 3 short-term tafoxiparin regimens (initial bolus 7, 21, or 35 mg followed by continuous infusion at 5, 15, or 25 mg/hour until delivery; maximum duration, 36 hours) in conjunction with oxytocin. Results: The number of participants randomized in study 1 was 263, and 361 were randomized in study 2. There were no statistically significant differences in the primary endpoints between those receiving tafoxiparin and those receiving the placebo in both studies. However, in study 1, the risk for having a labor time exceeding 12 hours was significantly reduced by tafoxiparin (tafoxiparin 6/114 [5%] vs placebo 18/101 [18%]; P=.0045). Post hoc analyses showed that women who underwent labor induction had a median (range) labor time of 4.44 (1.2–8.5) hours with tafoxiparin and 7.03 (1.5–14.3) hours with the placebo (P=.0041) and that co-administration of tafoxiparin potentiates the effect of oxytocin and facilitates a shorter labor time among women with a labor time exceeding 6 to 8 hours (P=.016). Among women induced into labor, tafoxiparin had a positive effect on cervical ripening in 11 of 13 cases (85%) compared with 3 of 13 participants (23%) who received the placebo (P=.004). For women requiring oxytocin because of slow progression of labor, the corresponding results were 34 of 51 participants (66%) vs 16 of 40 participants (40%) (P=.004). In study 2, tafoxiparin had no positive effects on the secondary endpoints when compared with the placebo. Except for injection-site reactions in study 1, adverse events were no more common for tafoxiparin than for the placebo among either mothers or infants. There were few serious or treatment-related adverse events. Conclusion: Subcutaneous treatment with tafoxiparin before labor onset (study 1) may be effective in reducing the labor time among women undergoing labor induction and among those requiring oxytocin for slow progression of labor. Moreover, tafoxiparin may have a positive effect on cervical ripening. Short-term, intravenous treatment with tafoxiparin as an adjunct to oxytocin in patients with labor arrest (study 2) did not affect labor time or other endpoints. Both studies suggest that tafoxiparin has a favorable safety profile in mothers and their infants.Peer reviewe

Exposure to specific tumour necrosis factor inhibitors and risk of demyelinating and inflammatory neuropathy in cohorts of patients with inflammatory arthritis : a collaborative observational study across five Nordic rheumatology registers

Funding Information: This work was supported by NordForsk and the Foundation for Research in Rheumatology (Foreum) and Vinnova. The research infrastructure was supported by funds from the Swedish Research Council, the Swedish Heart Lung Foundation and the Swedish Cancer Society, and funds from Region Stockholm-Karolinska Institutet (ALF). The Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY) (Norway) is funded as a Centre for Clinical Treatment Research by the Research Council of Norway (project 328657). Publisher Copyright: © 2023 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objective To compare incidences of neuroinflammatory events, including demyelinating disease (DML), inflammatory polyneuropathies (IPN) and multiple sclerosis (MS), in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA; including psoriatic arthritis) starting a tumour necrosis factor inhibitor (TNFi), investigating whether monoclonal TNFi antibodies (other TNFis (oTNFis)) confer higher risk than etanercept. Methods This is an observational cohort study including patients from the five Nordic countries starting a TNFi in 2001-2020. Time to first neuroinflammatory event was identified through register linkages. We calculated crude incidence rates (cIR) per 1000 person-years and used multivariable-adjusted Cox regression to compare incidences of neuroinflammatory events overall and for DML, IPN and MS with oTNFi versus etanercept. We further examined individual TNFis and indications. Results 33 883 patients with RA and 28 772 patients with SpA were included, initiating 52 704 and 46 572 treatment courses, respectively. In RA, we observed 135 neuroinflammatory events (65% DML) with cIR of 0.38 with oTNFi and 0.34 with etanercept. The HR of oTNFi versus etanercept was 1.07 (95% CI 0.74 to 1.54) for any neuroinflammatory event, 0.79 (95% CI 0.51 to 1.22) for DML, 2.20 (95% CI 1.05 to 4.63) for IPN and 0.73 (95% CI 0.34 to 1.56) for MS. In SpA, we observed 179 events (78% DML) with cIR of 0.68 with oTNFi and 0.65 with etanercept. The HR for any neuroinflammatory event, DML, IPN and MS was 1.06 (95% CI 0.75 to 1.50), 1.01 (95% CI 0.68 to 1.50), 1.28 (95% CI 0.61 to 2.69) and 0.94 (95% CI0.53 to 1.69), respectively. Conclusion The cIRs of neuroinflammatory events are higher in SpA than in RA, but the choice of specific TNFi does not seem to play an important role in the risk of neuroinflammatory events.Peer reviewe